Resveratrol (3,5,4-trihydroxy-trans-stilbene) is a phytoalexin compound with anti-inflammatory and antioxidant activities. The effect of resveratrol on swarming and virulence factor expression of Proteus mirabilis, an important pathogen infecting the urinary tract, was determined on swarming agar plates with and without the compound. Bacteria harvested at different times were assayed for cell length and the production of flagella, haemolysin and urease. Resveratrol inhibited P. mirabilis swarming and virulence factor expression in a dose-dependent manner. Resveratrol significantly inhibited swarming at 15 mg ml , and completely inhibited swarming at 60 mg ml "1 . Inhibition of swarming and virulence factor expression was mediated through RsbA, a His-containing phosphotransmitter of the bacterial two-component signalling system possibly involved in quorum sensing. Complementation of an rsbA-defective mutant with the rsbA gene restored its responsiveness to resveratrol. The compound also inhibited the ability of P. mirabilis to invade human urothelial cells. These findings suggest that resveratrol has potential to be developed as an antimicrobial agent against P. mirabilis infection.
INTRODUCTIONProteus mirabilis, a motile Gram-negative enteric bacterium, is an important pathogen of the urinary tract, and is the primary infectious agent in patients with indwelling urinary catheters (Warren et al., 1982). Individuals suffering from urinary tract infections caused by P. mirabilis often develop bacteriuria, cystitis, kidney and bladder stones, catheter obstruction due to stone encrustation, acute pyelonephritis, and fever (Burall et al., 2004;Johnson et al., 1993;Mobley & Warren, 1987).The ability of P. mirabilis to colonize the surfaces of catheters and the urinary tract is believed to be aided by a characteristic known as swarming differentiation and migration (Allison et al., 1994). P. mirabilis swarming involves the coordinate differentiation of short, motile, vegetative cells with a few peritrichous flagella into multinucleate, aseptate swarm cells of up to 40 times the vegetative cell length, and with more than a 50-fold greater surface density of flagella. The swarm cells migrate coordinately and rapidly away from the colony as multicellular rafts until they pause (consolidation) and undergo some de-differentiation (Allison & Hughes, 1991b; Rauprich et al., 1996). Regular cycles of migration and consolidation generate a colony on the agar surface with a characteristic pattern of concentric rings (Allison & Hughes, 1991b; Rauprich et al., 1996). Several potential virulence factors may be responsible for the pathogenicity of P. mirabilis. Among them, flagella, necessary for motility, are involved in establishing infection (Harmon et al., 1989). Urease, which is responsible for the formation of bladder and kidney stones at later stages of infection (Mobley & Hausinger, 1989), can facilitate the colonization of the urinary tract in a mouse model (Jones et al., 1990). Haemolysin, which is cytotoxic for cultured ur...
